The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway.
The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway.
复制标题
DOI：
10.1093/hmg/ddn325
复制
发表时间：
2009-01-01
影响因子：
3.5
通讯作者：
Henske, Elizabeth P.
中科院分区：
文献类型：
--
作者：
Hartman, Tiffiney R.;Liu, Dongyan;Zilfou, Jack T.;Robb, Victoria;Morrison, Tasha;Watnick, Terry;Henske, Elizabeth P.
结节性硬化症(TSC)是一种肿瘤抑制基因综合征，可发生严重的肾囊性疾病。许多肾囊性疾病，包括常染色体显性遗传性多囊肾病(ADPKD)，都与初级纤毛缺失或功能障碍有关。我们在这里报道了Hamartin(Tsc1)定位于初级纤毛的基底层，并且Tsc1−/−和Tsc2−/−小鼠胚胎成纤维细胞(MEF)比野生型对照更有可能含有初级纤毛。此外，TSC1−/−和TSC2−/−MEF的纤毛比野生型MEF的纤毛长17-27%。这些数据表明，TSC中存在一种新型的纤毛断裂，与纤毛发育增强有关。TSC1和TSC2蛋白作为异源二聚体抑制哺乳动物靶标雷帕霉素复合体1(TORC1)的活性。雷帕霉素不能抑制TSC1MEF和TSC2MEF的纤毛形成，提示TORC1MEF的纤毛形成不依赖−/−。多囊蛋白1(Polycystin 1，PC1)是PKD 1基因的产物，可与TSC2相互作用，但PKD 1−/−MEF不能促进纤毛的形成。此外，虽然在ADPKD患者的肾囊肿中观察到了mTOR的激活，但PKD1TSC MEF没有发现结构性mTOR激活的证据，从而强调了−/−蛋白和PC1在调节原发纤毛和mTOR中的独立功能。我们的数据将TSC蛋白与初级纤毛联系在一起，并揭示了一种新的表型，即在囊性疾病中纤毛形成增强。
Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome in which severe renal cystic disease can occur. Many renal cystic diseases, including autosomal dominant polycystic kidney disease (ADPKD), are associated with absence or dysfunction of the primary cilium. We report here that hamartin (TSC1) localizes to the basal body of the primary cilium, and that Tsc1−/− and Tsc2−/− mouse embryonic fibroblasts (MEFs) are significantly more likely to contain a primary cilium than wild-type controls. In addition, the cilia of Tsc1−/− and Tsc2−/− MEFs are 17–27% longer than cilia from wild-type MEFs. These data suggest a novel type of ciliary disruption in TSC, associated with enhanced cilia development. The TSC1 and TSC2 proteins function as a heterodimer to inhibit the activity of the mammalian target of rapamycin complex 1 (TORC1). The enhanced ciliary formation in the Tsc1−/− and Tsc2−/− MEFs was not abrogated by rapamycin, which indicates a TORC1-independent mechanism. Polycystin 1 (PC1), the product of the PKD1 gene, has been found to interact with TSC2, but Pkd1−/− MEFs did not have enhanced ciliary formation. Furthermore, while activation of mTOR has been observed in renal cysts from ADPKD patients, Pkd1−/− MEFs did not have evidence of constitutive mTOR activation, thereby underscoring the independent functions of the TSC proteins and PC1 in regulation of primary cilia and mTOR. Our data link the TSC proteins with the primary cilium and reveal a novel phenotype of enhanced ciliary formation in a cyst-associated disease.
登录
查看更多内容
影响因子：
6.5
作者：
Karbowniczek, Magdalena;Spittle, Cynthia S.;Henske, Elizabeth P.
通讯作者：
Henske, Elizabeth P.
影响因子：
10.5
作者：
Inoki, K;Li, Y;Guan, KL
通讯作者：
Guan, KL
影响因子：
3.5
作者：
Garcia-Gonzalez, Miguel A.;Menezes, Luis F.;Germino, Gregory G.
通讯作者：
Germino, Gregory G.
影响因子：
5.8
作者：
Chodhari, R;Mitchison, H M;Meeks, M
通讯作者：
Meeks, M
影响因子：
3.6
作者：
Kenerson, H;Dundon, TA;Yeung, RS
通讯作者：
Yeung, RS